Unknown

Dataset Information

0

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect.

ABSTRACT: In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking.

SUBMITTER: Qureshi YH 

PROVIDER: S-EPMC6168984 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect.

Qureshi Yasir H YH   Patel Vivek M VM   Berman Diego E DE   Kothiya Milankumar J MJ   Neufeld Jessica L JL   Vardarajan Badri B   Tang Min M   Reyes-Dumeyer Dolly D   Lantigua Rafael R   Medrano Martin M   Jiménez-Velázquez Ivonne J IJ   Small Scott A SA   Reitz Christiane C  

Molecular and cellular biology 20180928 20

In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which caus  ...[more]

Similar Datasets

Unknown The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking.
| S-EPMC6251589 | biostudies-literature
Unknown Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease.
| S-EPMC3779465 | biostudies-other
Unknown Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer's disease neurons.
| S-EPMC5886073 | biostudies-literature
Unknown ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease.
| S-EPMC4972530 | biostudies-literature
Unknown The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule-dependent trafficking.
| S-EPMC4621833 | biostudies-other
Unknown Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation.
| S-EPMC5000076 | biostudies-other
Unknown Hypoxia induced hERG trafficking defect linked to cell cycle arrest in SH-SY5Y cells.
| S-EPMC6481834 | biostudies-literature
Unknown Rab32 interacts with SNX6 and affects retromer-dependent Golgi trafficking.
| S-EPMC6331118 | biostudies-literature
Unknown The role of N-glycosylation in folding, trafficking, and functionality of lysosomal protein CLN5.
| S-EPMC3769244 | biostudies-literature
Unknown Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.
| S-EPMC7901670 | biostudies-literature